Radiation recall pneumonitis induced by PD-1/PD-L1 blockades: mechanisms and therapeutic implications

Abstract

Background The synergistic effect of radiotherapy (RT) in combination with immunotherapy has been shown in several clinical trials and case reports. The overlapping pulmonary toxicity induced by thoracic RT and programmed death 1/programmed death ligand-1 (PD-1/PD-L1) blockades is an important issue of clinical investigation in combination treatment. Thus far, the underlying mechanism of this toxicity remains largely unknown. Main text In this review, we discuss the unique pattern of radiation recall pneumonitis (RRP) induced by PD-1 blockade. The clinical presentation is different from common radiation pneumonitis (RP) or RRP induced by cytotoxic drugs. The immune checkpoint inhibitors may evoke an inflammatory reaction in patients’ previously irradiated fields, with infiltrating lymphocytes and potential involvement of related cytokines. All RRP patients have showed durable response to anti-PD-1/PD-L1. RRP is manageable; however, interruption of checkpoint blockades is necessary and immunosuppressive treatment should be started immediately. Further analyses of the predictive factors, including RT dosimetric parameters, tumor-infiltrating lymphocytes (TILs), and PD-L1 expression, are needed given the wide use of immune checkpoint inhibitors and high mortality from lung toxicity with the combination treatment. Conclusion Immune checkpoint inhibitors may evoke an RRP in the patients’ previously irradiated fields. Interactions between immune checkpoint inhibitors and radiotherapy should be studied further.

Radiation recall pneumonitis triggered by an immune checkpoint inhibitor following re-irradiation in a lung cancer patient: a case report

“…Radiological features of ICI-induced RRP include ground-glass or consolidative opacities confined to prior radiation field [ 10 ]. The most common radiographic patten of RRP is cryptogenic organizing pneumonia (COP) [ 11 ]. Artificial intelligence and radiomics have also emerged as promising tools to interrogate cancer images before, during and after treatment [ 12 ].…”

Innovative immunotherapy targeting at PD-1/PD-L1 signaling pathway: mechanism, efficacy and safety analysis of monotherapy and combination therapies in non-small cell lung cancer (NSCLC) treatment

“…Therefore, there might be a positive relationship between PD-L1 expression and immunotherapy-induced RRP, which conforms to its hypothesized mechanism that PD-1 blockade can free PD-L2 from PD-1 ligation increase its chance of binding to repulsive guidance molecule b (RGMb), leading to RRP. However, due to limited researches and data, we can still not tell a definitive relationship between the level of PD-L1 expression and the occurrence of immunotherapy-induced RRP [62].…”

Optimizing the Treatment Schedule of Radiotherapy Combined With Anti-PD-1/PD-L1 Immunotherapy in Metastatic Cancers

“…Pembrolizumab given concurrently with SBRT or HFRT confirmed no clinical benefits in the MDACC trial but two patients had grade 4 adverse event which might be related to the concurrent scheme ( 56 ). Anti-PD-1/PD-L1 therapy may also lead to radiation recall pneumonitis ( 74 ). In the clinical studies listed above, it seemed the time intervals between radiotherapy and anti-PD-1/PD-L1 therapy were not associated with the rate of severe pneumonitis.…”